Growth Hormone Use in Adolescents and Adults With Cystic Fibrosis

Summary

We hypothesize that the anabolic effects of growth hormone (GH) will improve the clinical
status of patients with CF by improving lean body mass, osteopenia, muscle strength,
pulmonary function, and quality of life.

We will recruit 40 malnourished CF patients for this 12-month study. All 40 patients will
be treated with recombinant human growth hormone (rhGH). Each patient will serve as his/her
own control by obtaining medical records for 6 months to 1 year prior to study enrollment or
by completing 6 months of study without GH prior to being treated for 1 yr. with GH.

Description

Patients will be treated with growth hormone in the form of Nutropin (a powder formulation
that is reconstituted by the patient) or Nutropin AQ (a ready-to-use liquid) for 1 year.
Both of these products are manufactured by Genentech, Inc. The starting dose will be 0.006
mg/kg given as a daily subcutaneous (SC) injection. The GH dose will be titrated 1-3 months
after GH initiation to maintain blood levels of IGF-1 within the normal range for age and
sex. The dose will be increased to a maximum of 0.025 mg/kg daily in adult patients <35
years and to a maximum of 0.0125 mg/kg daily in adult patients > 35 years. Pre-pubertal and
adolescent patients will be dosed at 0.3 mg/kg/wk to 0.6 mg/kg/wk.

PROCEDURES:

1. To determine the effect of GH on body weight and lean body mass in CF, weight will be
measured at baseline and every three months utilizing the same scale. LBM will be
measured at baseline and every six months by dual emission x-ray absorptiometry (DEXA)
scan.

2. To determine the effect of GH on protein breakdown and protein synthesis in CF, protein
turnover studies will be performed at baseline and every 6 months utilizing the stable
isotope C-leucine and mass spectrophotometric analysis.

Each subject will undergo 30-minute measurements of substrate oxidation and resting
energy expenditure using hood indirect calorimetry. Substrate calculations yielding
information on glucose oxidation and lipid oxidation will be determined using the
methods of de Weir, and results will be correlated with measurements calculated from
stable isotope infusion.

3. To determine the effect of GH on hepatic glucose production (HGP) the following study
will be performed at baseline and every 6 months.

4. To quantify the portion of hepatic glucose production (HGP) derived from
gluconeogenesis and glycogenolysis in the post-absorptive state. We will measure
gluconeogenesis using the stable isotope 2H2O and measurement of the incorporation of
2H into the 6th and 2nd carbon of glucose, according to the method of Landau 11.

5. To determine if GH improves the nutritional status of CF patients the following
nutritional status indicators will be measured at 6 month intervals: retinal binding
protein, transferrin, thyroxine binding prealbumin, albumin, and lipid profile.
Additionally, caloric intake and food group consumption will be analyzed by a skilled
dietitian from 3-day food journals recorded every six months.

6. To determine if GH improves the clinical condition of CF patients, participants will
perform pulmonary function tests, including measurement of PI and PE for estimation of
respiratory muscle strength. Additionally, each subject's clinical status will be
evaluated at baseline and every 3 months utilizing a modified NIH clinical status
scoring system.

7. To determine if GH improves the quality of life of CF patients, participants will
complete a 15-minute questionnaire to assess quality of life. This questionnaire
entitled "The Cystic Fibrosis Questionnaire" has been recently developed and tested for
quality. It is specific for CF patients and has been approved by the National CF
Foundation.

8. All patients will have random blood glucose testing per CF Foundation guidelines. If a
patient has previously undiagnosed cystic fibrosis related diabetes (CFRD) with or
without fasting hyperglycemia (FH), he/she will be treated with insulin for a minimum
for 3 months prior to study enrollment. Patients in all other glucose tolerance
categories will be allowed to participate in the study Also, patients previously
treated with insulin will be allowed to participate if HgbA1C is < 8.5%. If not, the
PI will adjust insulin and maximize glycemic control for 3 months before study entry.
Any patient who develops CFRD with or without FH will be continued in the study only if
he/she will agree to insulin therapy. If a patient refuses insulin therapy, he/she
will be discontinued from the study. Patients will continue to be screened for glucose
intolerance by measuring random blood glucose and HgbA1C.

9. To further study the sustained effect of GH, all study subjects will be given the
option of continuing on GH for an additional year. The same assessments above will be
performed every six months for the additional year.

Statistics:

This is a pilot study of 40 subjects. Data will be assessed as mean and standard deviation.
Data will then be used to compute a power analysis for a future larger study.
Non-treatment data will be compared to treatment data with emphasis on the 12 and 18-month
time points. Data from patients who develop CFRD while on the study, if there are any, will
be analyzed separately from those who do not develop CFRD.

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Medical and Biotech [MESH] Definitions

Human Growth Hormone

A 191-amino acid polypeptide hormone secreted by the human adenohypophysis (PITUITARY GLAND, ANTERIOR), also known as GH or somatotropin. Synthetic growth hormone, termed somatropin, has replaced the natural form in therapeutic usage such as treatment of dwarfism in children with growth hormone deficiency.

An autosomal recessive disorder characterized by short stature, defective GROWTH HORMONE RECEPTOR, and failure to generate INSULIN-LIKE GROWTH FACTOR I by GROWTH HORMONE. Laron syndrome is not a form of primary pituitary dwarfism (GROWTH HORMONE DEFICIENCY DWARFISM) but the result of mutation of the human GHR gene on chromosome 5.

Dwarfism, Pituitary

A form of dwarfism caused by complete or partial GROWTH HORMONE deficiency, resulting from either the lack of GROWTH HORMONE-RELEASING FACTOR from the HYPOTHALAMUS or from the mutations in the growth hormone gene (GH1) in the PITUITARY GLAND. It is also known as Type I pituitary dwarfism. Human hypophysial dwarf is caused by a deficiency of HUMAN GROWTH HORMONE during development.

Growth Hormone

A polypeptide that is secreted by the adenohypophysis (PITUITARY GLAND, ANTERIOR). Growth hormone, also known as somatotropin, stimulates mitosis, cell differentiation and cell growth. Species-specific growth hormones have been synthesized.

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